Treatment of chronic inflammatory joint disease with arylsulfonamides

ABSTRACT

A method of treating chronic inflammatory joint disease with arylsulfonamides of the formula: 
     
         Z--SO.sub.2 NR.sup.1 R.sup.2 
    
     wherein R 1  and R 2  are selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, loweralkylphenyl, 2 or 3 pyrrolidinyl, 2 or 3-(N-loweralkylpyrrolidinyl, or R 1  and R 2  taken together may form pyrrolidinyl or piperidinyl heterocyclic amino radicals and Z is an aryl group selected from substituted or unsubstituted tetrazole, 1,3,4-thiadiazole, 1,2,4-triazole, benzothiazole, benzimidazole, imidazole, pyridyl, 4,6-dimethyl pyrimidine, benzene or naphthalene is disclosed.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention is concerned with the use of certainarylsulfonamides in the treatment of joint disease associated withchronic arthritis methods and pharmaceutical compositions therefore. Inparticular the invention is concerned with internal administration ofcertain arylsulfonamides to arthritic mammals for the purpose ofinhibiting joint degeneration.

A major consequence of chronic inflammatory joint disease (rheumatoidarthritis) and degenerative arthritis (osteoarthritis) is loss offunction of those affected joints. This loss of function is due todestruction of the major structural components of the joint, cartilageand bone, and subsequent loss of the proper joint anatomy. Destructionof the architecture of the joint is due to a complex interaction ofcells and mediators found in the synovial fluid, synovial membrane, boneand cartilege of the joint. In the case of rheumatoid arthritis, theinflamed synovium thickens, forms a pannus, and this invading pannuserodes the underlying cartilage and bone. In osteoarthritis, destructionappears to be mediated by the bone and cartilage cells themselves. Ineither case, as a consequence of chronic disease, joint destructionensues and can lead to irreversible and permanent damage to the jointand loss of function.

2. Information Disclosure Statement

Heretofore it has not been recognized in the arts of pharmacology andmedicine that arylsulfonamides have utility in treatment of jointdeterioration associated with chronic arthritis.

Clinical tests administering acetazolamide percutaneously for treatmentof painful cellulitic edema to patients of several types, including someafflicted with degenerative joint disease, have been reported by Marc deSeze, et al in Sem. Hop. Paris Ther. 53(2)91-94(1977). Certainimprovements to cellulalgia or inflammatory cellulitis conditions werenoted; however, there is no teaching or evidence presented thatacetazolamide was used to treat degenerating joints or that it could beused for that indication.

A number of the arylsulfonamides useful in the method of invention aredisclosed in several patents as referred to hereinbelow in descriptionof various aspects and scope of the method of the present invention andfor reference to preparation of the compounds, which patents, namelyU.S. Pat. Nos. 2,608,507, 2,554,816, 2,721,204, 2,783,241, 2,835,702,2,980,679 and British Pat. No. 795,174 are all hereby incorporated byreference.

OBJECTS AND SUMMARY OF THE INVENTION

This invention is based on the discovery that certain arylsulfonamideshave utility for inhibiting damage to bone and joints in mammalssuffering from chronic arthritis. In the test procedure used chronicarthritis in rats is established by administering Freund's adjuvant intoa hind foot and thereafter observing the effect of administration ofarylsulfonamides on joint structure by means of x-ray photography andmeasurement of hind paw volumes. Illustrative of compounds useful in themethod of treatment of this invention, but not limited thereto are:acetazolamide, methazolamide, ethoxzolamide, benzolamide,dichlorphenamide, probenecid, and generic relatives of all. Aparticularly useful compound for the instant method is acetazolamide. Itis therefore a primary object of the invention to provide a method oftreating joint degeneration including alleviating and preventing jointdegeneration associated with chronic arthritis in living animals byinternally administering certain arylsulfonamides.

Another object is to use the arylsulfonamides in pharmaceuticalcompositions for treating, alleviating and preventing joint degenerationin living animals.

Still other objects will become apparent to one skilled in the arts ofpharmacology and medicine.

DETAILED DESCRIPTION OF THE INVENTION

A general class of compounds found to have capability of inhibitingjoint degeneration in arthritic animals is that of aromaticsulfonamides. The structure of this group is generally expressed by theformula:

    Z--SO.sub.2 NR.sup.1 R.sup.2                               Formula 1

wherein

R¹ and R² are selected from hydrogen, loweralkyl, loweralkenyl,cycloalkyl, phenyl, loweralkylphenyl, 2 or 3-pyrrolidinyl, 2 or3-(N-loweralkyl)-pyrrolidinyl or R¹ and R² taken together with nitrogenmay form pyrrolidinyl or piperidinyl heterocylic amino radicals;

Z is an aryl group selected from: ##STR1##

X is N or CR³ ;

Y is S or NR⁴ ;

and X, Y may be part of a fused ring system in which the 5-membered ringcontaining X and Y forms a ring fused with a 6-membered heterocylic ringsuch as pyridine;

R³ is selected from

hydrogen,

aminosulfonyl,

loweralkylcarbonylamino

2-haloacetylamino,

2-trihaloacetylamino,

phenylcarbonylamino,

phenylsulfonylamino

p-acetylaminophenylsulfonylamino,

halophenylsulfonylamino,

dihalophenylsulfonylamino,

p-aminophenylsulfonylamino,

toluylsulfonylamino or

2-acetylamino-1,3,4-thiadiazoylsulfonylamino;

R⁴ is selected from hydrogen, phenyl, loweralkyl, phenylloweralkyl orpyrido;

R⁵ is selected from

acetylimino,

2-haloacetylimino,

2-trihaloacetylimino,

or phenylcarbonylimino;

R⁶ is selected from

hydrogen

loweralkyl

or phenylloweralkyl;

R⁷ is selected from hydrogen, loweralkyl, loweralkoxy or acetamido;

R⁸, R⁹ and R¹⁰ are selected from

hydrogen,

nitro,

amino,

halo,

loweralkyl,

hydroxy,

loweralkoxy,

aminoloweralkyl,

--SO₂ NR¹ R², wherein R¹ and R² are as defined above,

--C(O)OH,

--C(O)Oloweralkyl,

--C(O)Ophenyl,

--C(O)phenyl

R¹¹ is selected from hydrogen, hydroxyl or loweralkyl

R¹² is selected from

hydrogen,

loweralkyl,

phenyl

or phenylloweralkyl

R¹³ is selected from hydrogen or loweralkyl

R¹⁴ is selected from

acetylamino,

loweralkyl

or halo

and the pharmaceutically acceptable salts which form as a result of acidaddition to a basic amine group, when present, or metal salts of carboxygroups when present.

In the further definition of symbols in the formulas hereof and wherethey appear elsewere throughout the specification and in the claims, theterms have the following significance:

The term "loweralkyl" as used herein, unless otherwise specifiedincludes straight and branched hydrocarbon chain radicals of up to eightcarbons inclusive and is exemplified by such groups as methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl,heptyl and octyl radicals and the like. The term "loweralkoxy" has theformula O-loweralkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing 3-9 carbon atoms inclusive and includes such groupsas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl,cycloheptyl and the like.

The term "halo" when referred to herein includes fluorine, chlorine,bromine and iodine.

The term "phenyl" when used alone or in conjunction with loweralkyl asin "phenylloweralkyl" in the general formula definition is intended tomean unsubstituted phenyl or phenyl substituted by up to three commonradicals illustrated by loweralkyl, halo, nitro, and loweralkoxy withthe proviso that no more than two nitro groups or one stericallyhindering group illustrated by tert-butyl are present on phenyl at anyone time.

this invention is further described in greater detail by the followingspecific examples. Structures of the compounds of the examples areillustrated in the following descriptions and in Table 1. The scope ofthe invention is not limited to the examples, however.

Acetazolamide (Merck Index 10th Ed--45) and benzolamide (Merck Index 9thEd--1104) are representative of certain compounds encompassed by thestructure: ##STR2## which compounds are encompassed by Formula 1,wherein R¹, R², X and Y are as defined above under Formula 1. Thesecompounds of Formula 1a useful in the method of the present inventionillustrated by the following Examples 1-21 are the subject of U.S. Pat.Nos. 2,554,816 and 2,721,204 wherein methods of preparation aredescribed as follows:

U.S. Pat. No. 2,554,816--Examples 1-14

U.S. Pat. No. 2,721,204--Examples 15-21.

Additional illustrations are in Examples 22 and 23.

EXAMPLE NO.

1. 1,2,4-Triazole-3-sulfonamide.

2. 3-Hydroxy-4-phenyl-4,1,2-triazole-5-sulfonamide.

3. 4-Phenyl-4,1,2-triazole-3,5-disulfonamide.

4. 2-Acetylamino-1,3,4-thiadizole-5-sulfonamide, which is Acetazolamide.

5. 2-Amino-1,3-4-thiadiazole-5-sulfonamide.

6. 1,3,4-Thiadiazole-2,5-disulfonamide.

7. 2-Acetylamino-1,3-4-thiadiazole-5-sulfon-n-propylamide.

8. 2-Acetylamino-1,3,4-thiadiazole-5-sulfon-di-n-butylamide.

9. 2-Acetylamino-1,3,4-thiadiazole-5-sulfonbenzylamide.

10. 2-Acetylamino-1,3,4-thiadiazole-5-sulfon-p-toluide.

11. 1-Methyl-5-tetrazolesulfonamide.

12. 1-Phenyl-5-tetrazolesulfonamide.

13. Pyrido[2,1-c]-s-triazole-3-sulfonamide.

14. Pyrido[2,1-c]-s-triazole-3-sulfon-p-toluide.

15. 2-Benzenesulfonamido-1,3,4-thiadiazole-5-sulfonamide which isBenzolamide.

16. 2-(p-Acetylaminobenzenesulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

17. 2-(p-Bromobenzenesulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

18. 2-(p-Chlorobenzenesulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

19. 2-(p-Toluenesulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

20. 2-(3,4-Dichlorobenzenesulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

21.2-(2-Acetylamino-1,3,4-thiadiazole-5-sulfonamido)-1,3,4-thiadiazole-5-sulfonamide.

EXAMPLE 22N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]-2-hydroxybenzamide.

Acetazolamide (50 g) was stirred and heated at reflux in 500 ml 3Nhydrochloric acid for half an hour. The cooled solution was made basicwith 50% sodium hydroxide. The precipitated white solid5-amino-1,3,4-thiadiazole-2-sulfonamide was collected (Compound 1, 28g). It was dried further at 70° C. in a vacuum oven overnight. To amixture of Compound 1 (4.5 g, 0.025 mole) and pyridine (2.42 ml, 0.03mole) in 70 ml acetonitrile was added acetylsalicyloyl chloride (98%, 5g, 0.025 mole). The reaction mixture warmed and became a clear solution.Solid deposits occurred slowly after stirring at room temperature for1/2 hour. After two hours the solvent was evaporated; the residue wastriturated with isopropyl alcohol/water for two hours and then filtered,rinsed in succession with isopropyl alcohol/water, isopropylalcohol/isopropyl ether, 2×isopropyl ether. From the combined motherliquor and rinsings, a second crop was collected. Both the first andsecond crops were combined and dissolved in 50 mlN-methyl-2-pyrrolidone. The solution was filtered and the filtrate wastreated with 15 ml 3N hydrochloric acid at 70° C. for half an hour. Upondilution with 200 ml water, a white solid precipitated. The solid wascollected, rinsed with water, and dried in a vacuum over at 80° C.overnight to 4.4 g of title compound, mp>250° C.

Analysis: Calculated for C₉ H₈ N₄ O₄ S₂ : C, 36:00; H, 2.69; N, 18.66.

Found: C, 36.92; H, 2.86; N, 18.16.

EXAMPLE 23 N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]benzamide.

Compound 1 (4.5 g, 0.025 mole) prepared in the preceding example wasreacted with benzoyl chloride in the same manner as described forreaction with acetylsalicyloyl chloride in that example. The reactionmixture was concentrated and the residue was triturated in 6Nhydrochloric acid. About 6 g of solid was collected by filtration anddissolved in 400 ml boiling methanol. The solution was filtered hot, andthen concentrated to about half of the volume. The white solid obtainedon cooling was collected, and recrystallized in methanol to give 3.08 gof white solid, mp 250° C.

Analysis: Calculated for C₉ H₈ N₄ O₃ S₂ : C, 38.02; H, 2.84; N, 19.71.

Found: C, 38.05; H, 2.82; N, 19.64.

Methazolamide (Merck Index 10th--5824) is representative of anothergroup of compounds encompassed by the structure: ##STR3## whichcompounds are encompassed by Formula 1, wherein R¹, R², R⁵ and R⁶ are asdefined above under Formula 1. Preparation of compounds of Formula 1b,useful in the method of the present invention, illustrated by thefollowing Examples 24-34 are prepared as described in U.S. Pat. No.2,783,241.

EXAMPLE NO.

24. 5-Acetylimino-4-methyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide whichis methazolamide.

25. 5-Acetylimino-4-benzyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

26. 5-Acetylimino-4-ethyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

27. 5-Propionylimino-4-methyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

28. 5-Propionylimino-4-ethyl-Δ² -1,3,4-thiazoline-2-sulfonamide.

29. 5-Formylimino-4-methyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

30. 5-Butyrylimino-4-methyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

31. 5-Butyrylimino-4-benzyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

32. 5-Acetylimino-4-p-nitrobenzyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

33. 5-Acetylimino-4-butyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

34. 5-Propionylimino-4-butyl-Δ² -1,3,4-thiadiazoline-2-sulfonamide.

Ethoxzolamide (Merck Index 10th Ed.--3704) is representative of anothergroup of compounds encompassed by the structure: ##STR4## whichcompounds are encompassed by Formula 1 wherein R¹, R² and R⁷ are asdefined above under Formula 1. Preparation of compounds of Formula 1cuseful in the method of the present invention illustrated by thefollowing Examples 35-36 are prepared as described in British patentspecification No. 795,174.

35. 6-Ethoxy-2-benzothiazolesulfonamide which is ethoxzolamide.

36. 6-Acetamidobenzothiazole-2sulfonamide.

Dichlorphenamide (Merck Index 10th Ed.--3062) and Probenecid (MerckIndex 10th Ed.--7656) are representative of compounds encompassed by thestructure: ##STR5## which compounds are encompassed by Formula 1, andwherein R¹, R², R⁸, R⁹ and R¹⁰ are as defined under Formula 1.Preparation of compounds of the dichlorphenamide type, i.e. having twofulonamide groups as in the following examples 37 and 38, are describedin U.S. Pat. No. 2,835,702.

37. 4,5-Dichlorobenzene-1,3-disulfonamide.

38. 5-Bromo-4-chlorobenzene-1,3-disulfonamide which is Dichlorphenamide.

Other disulfonamides were prepared as described below, e.g. Examples 77and 78.

The preparation of compounds of Formula 1d bearing a carboxylic acidgroup on phenyl are described in U.S. Pat. No. 2,608,507. These andother compounds of Formula 1d in the following examples were purchasedor prepared. Reference to a company are to purchase of the compound fromthat company.

39. 4-N,N-Diethylsulfamyl benzoic acid, mp 195°-196° C.

40. 4-Di-n-butylsulfamyl benzoic acid, mp 160°-162° C.

41. N,N-Di-n-propyl-3-nitro-4-toluenesulfonamide, mp 54°-56° C.

42. 3-Amino-4-toluenesulfonyl piperidine, mp 117°-119° C.

43. N-Cyclohexyl-3-nitro-4-tolylsulfonamide, mp 96°-97° C.

44. 2-Nitro-4-N,N-di-n-propylsulfamylbenzoic acid, mp 152°-154° C.

45. 2-Amino-4-di-n-propylsulfamylbenzoic acid, 196°-197.5° C.

46. N-Allyl-3-nitro-4-toluenesulfonamide, mp 72°-73° C.

47. 3-Nitro-4-toluenesulfonamide, mp 144°-145° C.

48. 3-Amino-4-toluenesulfonamide, mp 175°-176° C.

49. 4-(Di-n-propylsulfamyl)-salicylic acid, mp 122°-123° C.

50. N,N-Dimethyl-3-nitro-4-toluenesulfonamide, mp 90°-9l.5° C.

51. N-Isopropyl-3-nitro-4-toluenesulfonamide, mp 72°-73.5° C.

52. 3-N-Acetamido-4-toluenesulfonamide, mp 231°-232° C.

53. 3-Hydroxy-4-toluenesulfonamide, 194°-196° C.

54. N',N'-Dimethyl-3-amino-4toluenesulfonamide, mp 172°-174° C.

55. Cyclohexyl-3-amino-4-toluenesulfonamide hydrochloride, mp 91°-92.5°C.

56. 2-Amino-4-isopropylsulfamylbenzoic acid, mp 218°-220° C.

57. 4-Isopropylsulfamyl-salicyclic acid, mp 195°-197° C.

58. 4-Carboxy-3-nitrobenzenesulfonamide, mp 192.5°14 196° C.

59. N-(1-Ethyl-3-pyrrolidinyl)-4-toluenesulfonamide hydrochloride, mp123°-125° C.

60. N,N-Di-n-butyl-4-pentyl-benzenesulfonamide.

60. 5-Aminosulfonyl-2-methoxybenzoic acid, mp 218°-220° C.

62. 5-Aminosulfonyl-2-methoxybenzoic acid, ethyl ester, mp 147°-149.5°C.

63. 4-[(Dipropylamino)sulfonyl]benzoic acid which is Propenecid.

64. 4-Amino-benzenesulfonamide.

65. Benzenesulfonamide, mp 151°-153° C.; Aldrich Chem. Co. Inc.

66. 4-Methylbenzenesulfonamide mp 136°-138° C.; Aldrich Chem Co. Inc.

67. 4-Nitrobenzenesulfonamide, mp 163°-165° C.; Aldrich Chem. Co. Inc.

68. 4-Chlorobenzenesulfonamide, mp 144°-146° C., Aldrich Chem. Co. Inc.

69. 2-Aminobenzenesulfonamide, mp 150°14 153° C.; Aldrich Chem. Co. Inc.

70. N,4-Dimethylbenzenesulfonamide, mp 76°14 79° C.; Aldrich Chem. Co.Inc.

EXAMPLE 71 3-Benzoylbenzenesulfonamide

A mixture of 9.9 g (0.05 mole) of 3-aminobenzophenone, 100 ml of aceticacid and 11 ml of concentrated hydrochloric acid and 20 g of ice wasdiazotized at 5°-10° C. by the dropwise addition of 3.5 g (0.05 mole) ofsodium nitrate in 5 ml of water over a 30-minute period. The diazotizedsolution was added to approximately 25 g of sulfur dioxide in 100 ml ofacetic acid containing 1 g of CuCl₂ in 5 ml of water. The mixture wasstirred for 2 hours, the diluted with 300 ml of water. The black oil wasseparated by decanting the aqueous layer and the oil was dissolved inacetone. The acetone solution was treated with 100 ml of concentratedammonium hydroxide then concentrated on a rotovaporator to removeacetone, leaving a brown precipitate in the concentrated ammoniumhydroxide. This brown precipitate was collected and recrystallized fromisopropyl alcohol to give 8.7 g (67 %) of title compound as tan plates,mp 150.5°-152° C.

Analysis: Calculated for C₁₃ H₁₁ NO₃ S: C, 59.76; H, 4.24; N, 5.36.

Found: C, 59.87; H, 4.28; N, 5.37.

EXAMPLE 72 5-(Aminosulfonyl)-2-hydroxybenzoic acid

A mixture of 2-methoxy-5-sulfamoylbenzoic acid (58 g, 0.25 mole), 48%hydrobromic acid (150 ml), and acetic acid (150 ml) was heated to refluxfor five hours. The progress of reaction was checked by thin layerchromatography (silica gel, 7:2:1 ethylacetate/methanol/29% ammoniumhydroxide). Upon cooling, a solid crystallized out which was collectedby filtration, and rinsed with cold water. This solid was dissolved inhot water (≦85° C.) and filtered through Celite® and recrystallized fromthe cool filtrate. Some of the recrystallized material was crystallizedonce more by dissolving in methanol, filtering, and mixing with excessamount of 1,1,1-trichloroethane. The mixture was evaporated to removemost of the methanol, and the resulting crystallizing mixture wasstirred in ice bath. The solid was collected by filtration and rinsedwith 1,1,1-trichloroethane, vacuum pumped at room temperature overnightto give a white solid, mp 234°-235° C.

Analysis: Calculated for C₇ H₇ NO₅ S: C, 38.71; H, 3.25; N, 6.45.

Found: C, 38.53; H, 3.19; N, 6.41.

EXAMPLE 73 2-(Acetyloxy)-5-(aminosulfonyl)benzoic acid hemihydrate

5-(Aminosulfonyl)-2-hydroxybenzoic acid (9.35 g, 0.043 mole) wassuspended in 50 ml acetonitrile. Pyridine (4.04 ml, 0.05 mole) was addedwith stirring. The resulting solution was chilled in an ice bath.Acetylchloride (3.63 ml, 0.05 mole) was added dropwise in two minutesand the reaction mixture was stirred at room temperature for four hours.To the reaction mixture was added about 50 ml each of ethyl acetate andsodium chloride solution. The organic layer was separated and extractedonce more with sodium chloride solution. The aqueous layers were backextracted with acetonitrile-ethyl acetate. The organic layers werecombined, dried over sodium sulfate, filtered, and concentrated to awhite solid. The solid was triturated in ethyl acetate and isopropylether with small amount of acetonitrile overnight. The solid wascollected, rinsed and dried under vacuum pump pressure to give 5.03 g oftitle compound, mp 179°-181° C.

Analysis: Calculated for C₉ H₉ NO₆ S.0.5 H₂ O: C, 40.30; H, 3.76; N,5.22.

Found: C, 40.95; H, 3.45; N, 5.48.

EXAMPLE 74 4-(Aminosulfonyl)benzoic acid methyl ester

A slurry of 30.2 g (0.15 mole) of p-carboxybenzenesulfonamide in 500 mlof methanol was treated with 30 g of anhydrous hydrogen chloride and themixture was heated at reflux temperature for 3 hr. The solution wasconcentrated under vacuum to give 32.3 g of white, crystalline residue.A 5.0 g portion of this residue was recrystallized from 25 ml ofmethanol to give 3.3 g of title compound as a white powder, mp 174°-178°C.

Analysis: Calculated for C₈ H₉ NO₄ S: C, 44.65; H, 4.22; N, 6.51.

Found: C 44.80; H, 4.30; N, 6.47.

EXAMPLE 75 4-(Aminosulfonyl)benzoic acid ethyl ester

A slurry of 10.0 g (0.05 mole) of p-carboxybenzenesulfonamide in 200 mlof absolute ethanol was treated with 10 g of anhydrous hydrogen chlorideand heated at reflux for 5 h to give, after crystallization from ethylacetate/petroleum ether, 10.6 g (93%) of white powder, mp 102°-104° C.

Analysis: Calculated for C₉ H₁₁ NO₄ S: C, 47.15; H, 4.84; N, 6.11.

Found: C, 47.06; H, 4.89; H, 6.08.

EXAMPLE 76 4-(Aminosulfonyl)benzoic acid pentyl ester

A slurry of 32.1 g (0.15 mole) of p-carboxybenzenesulfonamide, methylester in 400 ml of n-pentanol was treated with 25 g of anhydroushydrogen chloride and the mixture was heated at reflux temperature for 4hr. The reaction was again treated by the slow addition of anhydroushydrogen chloride during 8 hr of slow distillation. Approximately 150 mlof distillate was collected. The distillate was replaced in the reactionmixture with 150 ml of n-pentanol and the solution was heated at refluxfor 66 hr. Excess pentanol and hydrogen chloride were removed bydistillation under vacuum. The residue wad crystallized from a mixtureof 350 ml of ethyl acetate and 500 ml of petroleum ether to give 22.0 g(54%) of white flakes, mp 96°-98° C.

Analysis: Calculated for C₁₂ H₁₇ NO₄ S: C, 53.12; H, 6.32; N, 5.16.

Found: C, 53.00; H, 6.41; N, 5.19.

EXAMPLE 77 N-(1-Methylethyl)-1,4-benzenedisulfonamide

The reaction flask was charged with 7.1 g (0.12 mole) of isopropylaminein 50 ml methylene chloride. A 10 g (0.039 mole) sample of4-(sulfonyl)benzenesulfonyl chloride prepared by a procedure describedin J. Med. Chem., Vol. 6, pp. 307-11 (1963) was added in small portionsallowing the temperature to rise uncontrolled. The mixture was stirredat room temperature for three hours then concentrated to a thickresidue. The residue was slurried with 50 ml water to give a whitesolid. The solid was collected and dried. The weight of solid obtainedwas 5.4 g (50% yield), mp 165°-168° C. A recrystallization from 190proof ethanol (3 ml/g) and water (3 ml/g) gave 5.0 g of title compound,mp 166°-168° C.

Analysis: Calculated for C₉ H₁₄ N₂ O₄ S₂ : C, 38.84; H, 5.07; N, 10.06.

Found: C, 38.88; H, 5.00; N, 10.04.

EXAMPLE 78 N-Butyl-1,4-benzenedisulfonamide

The reaction flask was charged with 10 g (0.039 mole) of4-(sulfonyl)benzenesulfonyl chloride prepared by a procedure describedin J. Med. Chem., 6 pp. 307-11 (1963) in 7 ml acetonitrile. A droppingfunnel was charged with 8.8 g (0.12 mole) of butylamine and the aminewas added dropwise, allowing the temperature to rise. The mixture wasstirred for three hours and then concentrated to a thick residue. Theresidue was slurried with 100 ml water and the mixture filtered tocollect a white solid. After drying, the weight of solid was 8.0 g (70%yield), mp 164°-167° C. A recrystallization from 190 proof ethanol (4ml/g) and water (4 ml/g) gave 6.6 g of title compound, mp 170°-172° C.

Analysis: Calculated for C₁₀ H₁₆ N₂ O₄ S₂ : C, 41.08; H, 5.52; N, 9.58.

Found: C, 41.01; H, 5.40; N, 9.46.

Compounds of Formula 1 wherein Z has the structure: ##STR6## areillustrative prepared by the procedures of U.S. Pat. No. 2,980,679 andare represented in Examples 79-82 as follows:

Example 79. 1-Phenylimidazole-2-sulfonamide.

Example 80. Benzimidazole-2-sulfonamide.

Example 81. 5-Acetylamino-pyridine-2-sulfonamide.

Example 82. 4,6-Dimethyl-pyrimidine-2-sulfonamide.

Example 83. 5-Hydroxy-1-naththalenesulfonamide, m.p. 255-257 waspurchased from Aldrich Chem. Co.

                                      TABLE 1                                     __________________________________________________________________________    ZSO.sub.2 NR.sup.1 R.sup.2                                                    __________________________________________________________________________     ##STR7##                                                                     Example No.                                                                          X                Y    R.sup.1  R.sup.2                                 __________________________________________________________________________     1                                                                                    ##STR8##                                                                                       ##STR9##                                                                          H        H                                        2                                                                                    ##STR10##                                                                                      ##STR11##                                                                         H        H                                        3                                                                                    ##STR12##                                                                                      ##STR13##                                                                         H        H                                        4                                                                                    ##STR14##       S    H        H                                        5                                                                                    ##STR15##       S    H        H                                        6                                                                                    ##STR16##       S    H        H                                        7                                                                                    ##STR17##       S    C.sub.3 H.sub.7                                                                        H                                        8                                                                                    ##STR18##       S    C.sub.4 H.sub.9                                                                        H                                        9                                                                                    ##STR19##       S    CH.sub.2 C.sub.6 H.sub.5                                                               H                                       10                                                                                    ##STR20##       S    4-CH.sub.3C.sub.6 H.sub.5                                                              H                                       11     N                                                                                               ##STR21##                                                                         H        H                                       12     N                                                                                               ##STR22##                                                                         H        H                                       13                                                                                    ##STR23##            H        H                                       14                                                                                    ##STR24##            4-CH.sub.3C.sub.6 H.sub.5                                                              H                                       15                                                                                    ##STR25##       S    H        H                                       16                                                                                    ##STR26##       S    H        H                                       17                                                                                    ##STR27##       S    H        H                                       18                                                                                    ##STR28##       S    H        H                                       19                                                                                    ##STR29##       S    H        H                                       20                                                                                    ##STR30##       S    H        H                                       21                                                                                    ##STR31##       S    H        H                                       22                                                                                    ##STR32##       S    H        H                                       23                                                                                    ##STR33##       S    H        H                                       __________________________________________________________________________     ##STR34##                                                                    Example No.                                                                             R.sup.5   R.sup.6    R.sup.1                                                                          R.sup.2                                     __________________________________________________________________________    24        CH.sub.3 C(O)N                                                                          CH.sub.3   H  H                                           25        CH.sub.3 C(O)N                                                                          C.sub.6 H.sub.5 CH.sub.2                                                                 H  H                                           26        CH.sub.3 C(O)N                                                                          C.sub.2 H.sub.5                                                                          H  H                                           27        C.sub.2 H.sub.5 C(O)N                                                                   CH.sub.3   H  H                                           28        C.sub.2 H.sub.5 C(O)N                                                                   C.sub.2 H.sub.5                                                                          H  H                                           29        HC(O)N    CH.sub.3   H  H                                           30        C.sub.3 H.sub.7 C(O)N                                                                   CH.sub.3   H  H                                           31        C.sub.3 H.sub.7 C(O)N                                                                   C.sub.6 H.sub.5 CH.sub.2                                                                 H  H                                           32        CH.sub.3 C(O)N                                                                          4-NO.sub.2C.sub.6 H.sub.4                                                                H  H                                           33        CH.sub.3 C(O)N                                                                          C.sub.4 H.sub.9                                                                          H  H                                           34        C.sub.2 H.sub.5 C(O)N                                                                   C.sub.4 H.sub.9                                                                          H  H                                           __________________________________________________________________________     ##STR35##                                                                    Example No.    R.sup.7     R.sup.1                                                                          R.sup.2                                         __________________________________________________________________________    35             C.sub.2 H.sub.5 O                                                                         H  H                                               36             CH.sub.3 C(O)NH                                                                           H  H                                               __________________________________________________________________________     ##STR36##                                                                    Example No.                                                                          R.sup.8 R.sup.9  R.sup.10                                                                         R.sup.1  R.sup.2                                   __________________________________________________________________________    37     3-SO.sub.2 NH.sub.2                                                                   4-Cl     5-Cl                                                                             H        H                                         38     3-SO.sub.2 NH.sub.2                                                                   5-Br     4-Cl                                                                             H        H                                         39     4-COOH  H        H  C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                           40     4-COOH  H        H  C.sub.4 H.sub.9                                                                        C.sub.4 H.sub.9                           41     3NO.sub.2                                                                             4-CH.sub.3                                                                             H  C.sub.3 H.sub.7                                                                        C.sub.3 H.sub.7                           42     3-NH.sub.2                                                                            4-CH.sub.3                                                                             H                                                                                 ##STR37##                                         43     3-NO.sub.2                                                                            4-CH.sub.3                                                                             H  C.sub.6 H.sub.11                                                                       H                                         44     4-COOH  3-NO.sub.2                                                                             H  C.sub.3 H.sub. 7                                                                       C.sub.3 H.sub.7                           45     4-COOH  3-NH.sub.2                                                                             H  C.sub.3 H.sub.7                                                                        C.sub.3 H.sub.7                           46     4-CH.sub.3                                                                            3-NO.sub.2                                                                             H  CH.sub.2CHCH.sub.2                                                                     H                                         47     4-CH.sub.3                                                                            3-NO.sub.2                                                                             H  H        H                                         48     4-CH.sub.3                                                                            3-NH.sub.2                                                                             H  H        H                                         49     4-COOH  3-OH     H  C.sub.3 H.sub.7                                                                        C.sub.3 H.sub.7                           50     4-CH.sub.3                                                                            3-NO.sub.2                                                                             H  CH.sub.3 CH.sub.3                                  51     4-CH.sub.3                                                                            3-NO.sub.2                                                                             H  CH(CH.sub.3).sub.2                                                                     H                                         52     4-CH.sub.3                                                                            3-NHC(O)CH.sub.3                                                                       H  H        H                                         53     4-CH.sub.3                                                                            3-OH     H  H        H                                         54     4-CH.sub.3                                                                            3-NH.sub.2                                                                             H  CH.sub.3 CH.sub.3                                  55     4-CH.sub.3                                                                            3-NH.sub.3.sup.+ CL.sup.-                                                              H  C.sub.6 H.sub.11                                                                       H                                         56     4-COOH  3-NH.sub.2                                                                             H  CH(CH.sub.3).sub.2                                                                     H                                         57     4-COOH  3-OH     H  CH(CH.sub.3).sub.2                                                                     H                                         58     4-COOH  3-NO.sub.2                                                                             H  H        H                                         59     4-CH.sub.3                                                                            H        H                                                                                 ##STR38##                                                                             H                                         60     4-(CH.sub.2).sub.4 CH.sub.3                                                           H        H  C.sub.4 H.sub.9                                                                        C.sub.4 H.sub.9                           61     3-COOH  4-OCH.sub.3                                                                            H  H        H                                         62     3-COOC.sub.2 H.sub.5                                                                  4-OCH.sub.3                                                                            H  H        H                                         63     4-COOH  H        H  C.sub.3 H.sub.7                                                                        C.sub.3 H.sub.7                           64     4-NH.sub.2                                                                            H        H  H        H                                         65     H       H        H  H        H                                         66     4-CH.sub.3                                                                            H        H  H        H                                         67     4-NO.sub.2                                                                            H        H  H        H                                         68     4-Cl    H        H  H        H                                         69     2-NH.sub.2                                                                            H        H  H        H                                         70     4-CH.sub.3                                                                            H        H  CH.sub.3 H                                         71     3-C(O)C.sub.6 H.sub.5                                                                 H        H  H        H                                         72     3-COOH  4-OH     H  H        H                                         73     3-COOH  4-OC(O)CH.sub.3                                                                        H  H        H                                         74     4-COOCH.sub.3                                                                         H        H  H        H                                         75     4-COOC.sub.2 H.sub.5                                                                  H        H  H        H                                         76     4-COOC.sub.5 H.sub.11                                                                 H        H  H        H                                         77     4-SO.sub.2 NH.sub.2                                                                   H        H  CH(CH.sub.3).sub.2                                                                     H                                         78     4-SO.sub.2 NH.sub.2                                                                   H        H  C.sub.4 H.sub.9                                                                        H                                         __________________________________________________________________________     ##STR39##                                                                    Example No.  R.sup.12    R.sup.1 R.sup.2                                      __________________________________________________________________________    79           C.sub. 6 H.sub.5                                                                          H       H                                            __________________________________________________________________________     ##STR40##                                                                    Example No.   R.sup.13 R.sup.1  R.sup.2                                       __________________________________________________________________________    80            H        H        H                                             __________________________________________________________________________     ##STR41##                                                                    Example No.                                                                             R.sup.14                                                                              SO.sub.2 NR.sup.1 R.sup.2 Position                                                           R.sup.1                                                                           R.sup.2                                  __________________________________________________________________________    81        5-NHC(O)CH3                                                                           2              H   H                                        __________________________________________________________________________     ##STR42##                                                                    Example No.      R.sup.1     R.sup.2                                          __________________________________________________________________________    82               H           H                                                __________________________________________________________________________     ##STR43##                                                                    Example No.                                                                             R.sup.11                                                                          SO.sub.2 NH.sub.2 Position                                                                    R.sup.1                                                                             R.sup.2                                   __________________________________________________________________________    83        5-OH                                                                              1               H     H                                         __________________________________________________________________________

PHARMACOLOGICAL TEST PROCEDURES Test Procedure For Assessing JointDamage in Chronic Arthritic Rats

Adjuvant arthritis in female Lewis Wistar rats was induced using amodification of the method reported by Walz, D.T. et al. in J. Pharmac.Exp. Ther. 178, 223-231 (1971) by injection of 0.05 ml of a suspensionof 1.5% dead Mycobacterium butyricum in mineral oil into the subplantarsurface of the right hand paw. On Day 18 after adjuvant injection, thelimb volumes of both hind limb were determined. Rats with significantswelling of the uninjected hind limbs (<2.3 ml, volume measured bymercury displacement) were randomized into groups of seven. Subsequentdeterminations of paw edema and x-ray scores were made on the uninjectedhind limb. The rats were dosed orally daily beginning on Day 18 andcontinuing through Day 50 (excluding week-ends) after adjuvant injectionwith vehicle (0.5% Tween® 80, 10 ml/kg) or with vehicle and test drug.

Limb volumes were also recorded on Days 29 and 50 after adjuvantinjection and edema determined by volume difference compared to Day 18.The uninjected hind limb on each rat was x-rayed on Day 50 and the jointdamage assayed on an arbitrary scale of 1 to 10(1=no damage, 10=maximumdamage). Data on differences between control and treated groups (Day 29edema, Day 50 edema and Day 50 x-ray scores) were analyzed by using theDunnett's t-test (Dunnett, C.W. in J. Amer. Stat. Assoc. 50:1096-121,1955). Results for representative compounds of Formula 1 are given inTable 2. The results indicate that the compounds given once daily toarthritic rats produce consistent, significant anti-inflammatoryactivity (decreases in edema and decreases in x-ray score) when given atdoes of 3.16 mg/kg or higher.

                  TABLE 2                                                         ______________________________________                                        Effect of Formula I Compounds In Adjuvant-induced Arthritis(a)                in Female Lewis Wistar Rats                                                             Dose    Edema    Edema  X-Ray Number                                Compound +                                                                              mg/kg,  Day      Day    Score of                                    Vehicle   orally  29(b)    50(b)  (mean)                                                                              Animals                               ______________________________________                                         Control  --      0.19     -0.05  8.57  55                                    (Vehicle alone)                                                               Acetazolamide                                                                           3.16    -0.21*   -0.42* 6.30* 28                                              10.00   -0.32*   -0.53* 6.37* 35                                              31.6    -0.43*   -0.69* 6.79* 7                                     Methazolamide                                                                           3.16    -0.24*   -0.43* 6.71* 7                                     Ethoxzolamide                                                                           1.0     0.03*    -0.36* 6.89* 7                                               3.16    -0.29*   -0.43* 6.11* 7                                     Dichlorphen-                                                                            31.6    -0.10*   -0.34* 7.93* 14                                    amide     100.0   -0.29*   -0.54* 5.89* 7                                     ______________________________________                                         (a)Dosing took place daily, beginning on Day 18 after adjuvant injection      and continuing through Day 50 (excluding weekends  results are presented      as mean change in all experiments).                                           (b)Edema Day 29: Volume of Limb on Day 29 - Volume of Limb on Day 18          Edema Day 50: Volume of Limb on Day 50 - Volume of Limb on Day 18             *p < 0.05, Dunnett's Ttest.                                              

FORMULATION AND ADMINISTRATION

Compositions containing the active compounds of Formula 1 for jointdisease treatment may be internally administered to a living animal bodyin any one of various ways, for example, orally as in capsules ortablets, parenterally in the form of sterile solutions or suspensionsand in some cases intravenously in the form of sterile solutions. Informing the compositons, the active ingredient is incorporated in asuitable carrier, illustratively a pharmaceutical carrier. Suitablysolid pharmaceutical carriers which are useful in formulating thecompositions of this invention include starch, gelatin, glucose,magnesium carbonate, lactose, malt and the like. Liquid compositions maybe prepared using water, sugar syrups, ethyl alcohol, propylene glycol,glycerine, and the like.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampules and syrups are examples ofpreferred dosage forms. It is only necessary that the active ingredientconstitutes an effective amount, i.e. such that a suitable effectivedosage will be consistent with the dosage form employed. The exactdosages as well as daily dosages will of course be determined accordingto standard medical principles under the direction of a physician orveterinarian.

Based on animal screening tests it appears that unit dosages for humanscould be employed in the range of 0.1 to 150 milligrams. The unit dosagemay be given a suitable number of times daily so that the daily dosagefor an adult human may vary from 0.3 to 450 milligrams. Five to 50milligrams appears optimum per unit dose.

The active agents of the invention may be combined with otherpharmacologically active agents, or with buffers, antacids or the likefor administration and the proportion of the active agent in thecompositions may vary widely.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, methods, processes, andpharmaceutical compositions of the present invention without departingfrom the spirit and scope thereof, and it is therefore to be understoodthat the invention is to be limited only by the scope of the appendedclaims.

What is claimed is:
 1. A method of treating joint degenerationassociated with chronic arthritis in a living animal which comprisesinternally administering to said animal an effective amount for treatingjoint degeneration associated with chronic arthritis of anarylsulfonamide having the formula:

    Z--SO.sub.2 NR.sup.1 R.sup.2

wherein R¹ and R² are members selected from the group consisting ofhydrogen, loweralkyl, loweralkenyl, cycloalkyl, phenyl andloweralkylphenyl; Z is an aryl group selected from the group consistingof ##STR44## R³ is a member selected from the group consisting ofhydrogen, aminosulfonyl, loweralkylcarbonylamino, 2-haloacetylamino,2-trihaloacetylamino, phenylcarbonylamino, phenylsulfonylamino,p-acetylaminophenylsulfonylamino, halophenylsulfonylamino,dihalophenylsulfonylamino, p-aminophenylsulfonylamino andtoluylsulfonylamino; R⁴ is a member selected from the group consistingof acetylimino, 2-haloacetylimino, 2-trihaloacetylimino andphenylcarbonylimino; R⁵ is a member selected from the group consistingof hydrogen, loweralkyl and phenylloweralkyl; and the pharmaceuticallyacceptable salts which are formed as the result of an acid addition to abasic amine group, when said amine group is present or metal salts ofcarboxy groups when said carboxy groups are present.
 2. The methodaccording to claim 1, wherein the arylsulfonamide is acetazolamide. 3.The method according to claim 1, wherein the arylsulfonamide isbenzolamide.
 4. The method according to claim 1, wherein thearylsulfonamide is methazolamide.